192 Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients With Moderate to Severe Plaque Psoriasis: Pruritus and DLQI Correlations at Week 16 (ESTEEM 1 and 2) Steven R. Feldman, MD, PhD 1 ; Diamant Thaci, MD 2 ; Mark Ling, MD 3 ; Melinda Gooderham, MD, MSc 4 ; ChiaChi Hu, EdM, MS 5 ; Robert M. Day, PhD 5 ; Mark Goodfield, MD, FRCP 6 1 Wake Forest University School of Medicine, Winston-Salem, NC, USA; 2 University Hospital Schleswig-Holstein, Lübeck, Germany; 3 MedaPhase Inc., Newnan, GA, USA; 4 SKiN Centre for Dermatology, Peterborough, ON, Canada; 5 Celgene Corporation, Warren, NJ, USA; 6 Leeds General Infirmary, Leeds, UK Presented at: the 73rd Annual Meeting of the American Academy of Dermatology; March 2-24, 215; San Francisco, CA. This study was sponsored by Celgene Corporation.
Disclosures Dr. Steven R. Feldman has received honoraria and research grants as an investigator, speaker, and/or consultant for Abbott Labs, Amgen, Anacor Pharmaceuticals, Baxter, Caremark, Celgene, Galderma, Gerson Lehrman Group, Guidepoint Global, Hanall Pharmaceutical, Janssen, Kikaku, LEO Pharma, Lilly, Merck, Merz, Mylan, Novartis, Pfizer, Qurient, Stiefel/GSK, Suncare Research, Taro, and Xenoport; and has received royalties or owns stock in Causa Technologies, Informa Healthcare, Medical Quality Enhancement Corporation, UpToDate, and Xlibris Prof. Dr. Diamant Thaci has received honoraria as a speaker, advisory board member, and/or a consultant for Celgene, AbbVie, Amgen, Biogen-Idec, Dignity, Janssen-Cilag, LEO Pharma, Lilly, Maruho, Mitsubishi, Merck, Novartis, Pfizer, UCB, and XenoPort. Dr. Mark Ling has served as an investigator for AbbVie, Amgen, Celgene, Johnson & Johnson/Janssen, Pfizer, and Valeant and as an advisory board member for PhotoMedex. Dr. Melinda Gooderham has been an investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Eli Lilly, Galderma, Kyowa Hakko Kirin Pharma, LEO Pharma, Merck, Novartis, and Pfizer, and has served as a speaker for AbbVie, Amgen, Astellas, Galderma, Janssen, Leo Pharma, Novartis, and Pfizer. Ms. ChiaChi Hu and Dr. Robert M. Day are employees of Celgene Corporation. Dr. Mark Goodfield has received honoraria and research grants as an investigator and/or advisory board member for AbbVie, Celgene, Galderma, Janssen-Cilag, LEO Pharma, Novartis, and Pfizer.
Abstract Background: Itching is one of the most bothersome psoriasis symptoms. 1 ESTEEM 1 and 2 evaluated the effect of apremilast (APR) on itch in pts with moderate to severe plaque psoriasis. Methods: Pts (PASI 12, BSA 1%, spga 3 ) were randomized (2:1) to APR 3 mg BID (APR3) or placebo (PBO). At Wk16, PBO pts switched to APR3 through Wk32. This was followed by a randomized treatment withdrawal phase up to Wk52. The correlation of pruritus with health-related quality of life was explored using Spearman correlations between pruritus (VAS -1 mm; =no itch, 1=worst itch) and Dermatology Life Quality Index (DLQI) score (-3; 3=worst QOL) at baseline (BL) and Wk16. The results of pts who achieved minimal clinically important differences (MCID) in pruritus VAS score (improvement: 2%) 2 and DLQI score (improvement: 5 points [MCID] or score -1) 3 are summarized. Results: The full analysis set included 844 pts from ESTEEM 1 (PBO: n=282; APR3: n=562) and 411 from ESTEEM 2 (PBO: n=137; APR3: n=274). At Wk16, mean changes from BL in pruritus VAS (mm) scores were significantly greater with APR3 (ESTEEM 1: -31.5; ESTEEM 2: -33.5) vs PBO (ESTEEM 1: -7.3; ESTEEM 2: -12.2; P<.1). Mean changes from BL with APR3 represented a nearly 5% decrease in pruritus severity, and improvement in pruritus was observed as early as Wk2 (P<.1 vs PBO; post hoc analysis). At Wk16, MCID in pruritus VAS was achieved by significantly more pts receiving APR3 (ESTEEM 1: 7.6%; ESTEEM 2: 67.5%; P<.1) vs PBO (ESTEEM 1: 33.7%; ESTEEM 2: 4.9 %). Pruritus severity and DLQI scores were moderately correlated at BL (correlation coefficient,.55 [ESTEEM 1];.48 [ESTEEM 2]; P<.1). Improvement in pruritus correlated with an improvement in DLQI (correlation coefficient,.43 in either group, P<.1) in ESTEEM 1 and 2. At Wk16, MCID in pruritus VAS score and DLQI (decrease 5 points) were achieved by more pts receiving APR3 (ESTEEM 1: 46.4%; ESTEEM 2: 47.1%) than PBO (ESTEEM 1: 12.8%; ESTEEM 2: 24.8%). MCID in pruritus VAS score and a DLQI score of -1 were achieved by more pts with APR3 (ESTEEM 1: 25.1%; ESTEEM 2: 28.5%) vs PBO (ESTEEM 1: 5.3%; ESTEEM 2: 8.%). Conclusion: Improvements in pruritus were seen with APR3 as early as Wk2, and approximately 7% of patients achieved an MCID in pruritus VAS at Wk16. Improvement in pruritus severity was correlated with an improvement in QOL. 1. Lebwohl MG, et al. J Am Acad Dermatol. 214;7:871-81; 2. Reich A, et al. Acta Derm Venereol. 213;93:69-61; 3. Basra MKA, et al. Br J Dermatol. 28;159:997-135.
Introduction and Objective Psoriasis is a chronic, systemic inflammatory disease that affects 1% to 3% of the world s population. 1-3 Itching is one of the most bothersome psoriasis symptoms for patients and an important factor contributing to disease severity. 4 Apremilast, an oral PDE4 inhibitor, works intracellularly to regulate inflammatory mediators. 5 Apremilast was approved by the FDA in 214 and by the EC in 215 for the treatment of psoriasis and psoriatic arthritis. 6,7 ESTEEM is a phase 3 clinical trial program comprising 2 randomized, placebo-controlled studies evaluating the efficacy, safety, and tolerability of apremilast for the treatment of moderate to severe plaque psoriasis. The objective of the current analysis is to evaluate the effect of apremilast on pruritus and the correlation of pruritus with health-related quality of life* at Week 16 in ESTEEM 1 and ESTEEM 2. *As measured by the Dermatology Life Quality Index. EC=European Commission; ESTEEM=Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis; FDA=US Food and Drug Administration; PDE4=phosphodiesterase 4. 1. Helmick CG, et al. Am J Prev Med. 214;47:37-45; 2. Rachakonda TD, et al. J Am Acad Dermatol. 214;7:512-516; 3. Parisi R, et al. J Invest Dermatol. 213;133:377-385; 4. Lebwohl MG et al. J Am Acad Dermatol. 214;7:871-81. 5. Schafer P. Biochem Pharmacol. 212;83:1583-159; 6. Otezla [package insert]. Summit, NJ: Celgene Corporation, 214; 7. Otezla (apremilast) summary of product characteristics. Uxbridge, UK: Celgene Europe Ltd.; January 215.
Study Population Diagnosis of chronic plaque psoriasis, with moderate to severe plaque psoriasis at screening and baseline Pruritus and health-related quality of life (QOL) endpoints: Pruritus visual analog scale (VAS) 1 mm scale: =no itch at all, 1=worst itch imaginable Minimal clinically important difference (MCID): 2% improvement from baseline 1 Dermatology Life Quality Index (DLQI) 2 DLQI score to QOL impact bands (effect on QOL): o to 1=no effect, 2 to 5=small effect, 6 to 1=moderate effect, 11 to 2=very large effect, 21 to 3=extremely large effect 3,4 MCID: 5 points 3 1. Reich A, et al. Acta Derm Venereol. 213;93:69-61; 2. Finlay AY, et al. Clin Exp Dermatol. 1994;19:21-216. 3. Basra MKA, et al. Br J Dermatol. 28;159:997-135; 4. Hongbo Y, et al. J Invest Dermatol. 25 ;125:659-664.
Improvement in Pruritus VAS Score (mm) Over 16 Weeks Improvement in pruritus was observed as early as Week 2 with apremilast vs. placebo. At Week 16, decrease in pruritus was significantly greater with apremilast vs. placebo (ESTEEM 1: -31.5 mm vs. -7.3 mm; ESTEEM 2: -33.5 mm vs. -12.2 mm, both P<.1) These changes represent a decrease of ~5% from baseline in the severity of pruritus. Mean Change From Baseline in Pruritus VAS Score (mm) -1-2 -3-4 -5-6 -7 Study Week 4 14 8 12 16 * ESTEEM 1 ESTEEM 2 Placebo Apremilast 3 mg BID Placebo Apremilast 3 mg BID *P<.1 vs. placebo (post hoc analysis). Pruritus was measured on a 1-mm VAS. Baseline values: ESTEEM 1 65. mm (placebo) and 66.1 mm (apremilast 3 mg BID); ESTEEM 2 65.3 mm (placebo) and 67.7 mm (apremilast 3 mg BID). Data are as observed (figure) or last observation carried forward (bullet). In ESTEEM 1 at Week 16, n=248 (placebo) and n=5 (apremilast 3 mg BID); in ESTEEM 2 at Week 16, n=11 (placebo) and n=238 (apremilast 3 mg BID).
Pruritus VAS: MCID Achievement at Week 16 Patients Achieving MCID in Pruritus VAS (%) 8 * 7 6 5 4 3 2 1 *P<.1 vs. placebo. ESTEEM 1 ESTEEM 2 33.7 7.6 4.9 67.5 n = 282 562 137 274 Placebo Apremilast 3 mg BID MCID achievement in pruritus VAS is defined as an improvement of 2% over baseline. 1 Patients in the full analysis set with a non-zero baseline value and at least one post-baseline value using last observation carried forward are included. MCID=minimal clinically important difference; VAS=visual analog scale. ESTEEM 1 N=844; ESTEEM 2 N=411. 1. Reich A, et al. Acta Derm Venereol. 213;93:69-61. * Placebo Apremilast 3 mg BID
DLQI MCID Achievement at Week 16 ESTEEM 1 ESTEEM 2 Patients Achieving DLQI MCID at Week 16 (%) 8 * 7 6 5 4 3 2 1 7.2 7.8 42.9 33.5 * n = 236 459 119 226 Placebo Apremilast 3 mg BID Placebo Apremilast 3 mg BID *P<.1 vs. placebo. MCID achievement is defined as an improvement of 5 points in DLQI score over baseline. 1 Patients in the full analysis set with a baseline DLQI >5 are included, using last observation carried forward. ESTEEM 1=695; ESTEEM 2=345 1. Basra MKA, et al. Br J Dermatol. 28;159:997-135.
Change From Baseline in Pruritus VAS and DLQI With Apremilast 3 mg BID Over 16 Weeks At Week 16, decrease in DLQI score was significantly greater with apremilast vs. placebo (ESTEEM 1: -6.6 vs. -2.1; ESTEEM 2: -6.7 vs. 2.8, both P<.1). At Week 16, 46.4% of patients receiving apremilast achieved MCID for both pruritus and DLQI. Pruritus VAS (% Change From Baseline)* -1-2 -3-4 -5-6 -1-2 -3-4 -5-6 Study Week 4 8 12 16 Pruritus VAS % change MCID 1,2 ESTEEM 1 4 8 12 16 MCID 1,2 DLQI mean change ESTEEM 2 *Data for line graphs are based on patients with pruritus VAS 1 mm and DLQI 5. Baseline pruritus VAS values: ESTEEM 1 66.1 mm (apremilast); ESTEEM 2 67.7 mm (apremilast). Baseline DLQI scores: ESTEEM 1 12.7 (apremilast); ESTEEM 2 12.6 (apremilast). Reference line represents MCID, defined as an improvement of 5 points in DLQI score or an improvement of 2% in pruritus VAS from baseline. 1,2 1.Reich A, et al. Acta Derm Venereol. 213;93:69-61; 2. Basra MKA, et al. Br J Dermatol. 28;159:997-135. -2-5 -6-8 -1-12 -14-2 -5-6 -8-1 -12-14 DLQI (Mean Change From Baseline)*
Pruritus and DLQI Correlation Analyses Pruritus severity and DLQI scores were moderately correlated at baseline (correlation coefficient,.55 [ESTEEM 1] and.48 [ESTEEM 2]; P<.1). Improvement in pruritus correlated with an improvement in DLQI at Week 16 in ESTEEM 1 and 2 (correlation coefficient,.43 in either group, P<.1).* ESTEEM 1: Week 16 ESTEEM 2: Week 16 *Clustering in the left lower quadrant (denoted within the red square) demonstrates MCID improvement in both DLQI and pruritus. DLQI=Dermatology Life Quality Index; MCID=minimal clinically important difference; VAS=visual analog scale.
Overview of Safety Results (, Pooled) The most frequently reported AEs (>5%) during Period A (placebo-controlled period) were nausea, diarrhea, nasopharyngitis, URTI, tension headache, and headache. Most AEs were mild or moderate in severity and did not lead to discontinuation. Discontinuation rates due to AEs were low across treatment groups (placebo: 3.8%; apremilast: 5.4%). The incidence of serious AEs was low and comparable across treatment groups (placebo: 2.6%; apremilast: 2.%). Deaths (occurring in ESTEEM 1) were due to completed suicide (placebo) and cardiac failure (apremilast). Changes in laboratory parameters were transient and not clinically meaningful over time; no trend was observed. *Full analysis set includes all randomized patients who received 1 dose of study medication. AE=adverse event; URTI=upper respiratory tract infection.
Conclusions Improvements in pruritus and DLQI were consistent between both ESTEEM studies Improvements in pruritus were seen with apremilast 3 mg BID as early as Week 2. Approximately 7% of patients receiving apremilast 3 mg BID achieved an MCID in pruritus VAS at Week 16. Improvement in pruritus severity was correlated with an improvement in patient quality of life. At Week 16, approximately 46% of patients receiving apremilast 3 mg BID achieved MCID for both pruritus and DLQI. Apremilast 3 mg BID demonstrated an acceptable safety profile and was generally well tolerated.